Coccidioides immitis and C. posadasii, fungi endemic to the southwest United States, are regarded as potential bioterrorist weapons. Coccidioidomycosis results from inhalation of fungal spores. Dissemination to the CNS results in coccidioidal meningitis (CM) and 100% mortality if untreated and 40% mortality with present therapy. A new drug with a superior efficacy, safety profile, and administration is needed to safeguard against high morbidity and mortality stemming from wide-spread bioterrorist attacks. Viamet Pharmaceuticals, Inc., was founded on a technology platform expressly conceived to improve the pharmaceutical and safety properties of metallo-enzyme inhibitor drugs, including those of the cytochrome P450 (CYP) class. To our knowledge, the oral antifungal clinical candidate VT-1161 is the most potent and selective CYP51 antifungal compound described to date. It is currently in Phase I clinical studies in the U.S. prior to development as a treatment fr either invasive candidiasis or oncychomycosis. Furthermore, Viamet has a proprietary chemical library of over 700 CYP51 antifungal inhibitors that show differing potencies against diverse fungi including yeast, dermatophytes, molds, and plant pathogens. VT-1161 itself has in vitro activity against C. immitis and has excellent pharmacokinetic and CNS penetration properties. Therefore, VT-1161 likely would be effective for the treatment of CM. Given the chemical diversity and proven differential fungal activity, it is also likely that more potent Coccidioides leads are present in the Viamet chemical collection. The focus of this research proposal is a two-fold parallel approach. (1) VT-1161 will be tested in murine models of respiratory and CNS coccidioidomycoses, and if superior to standard of care, will then be tested in dogs with naturally occurring infections. (2) New anti-Coccidioides IND candidates more potent than VT-1161 will be identified by screening for and then optimizing hits that already exist within the Viamet chemical library and then commencing preclinical development of those candidates. The ultimate goal of this research is to identify a molecule (either VT-1161 or a novel Viamet antifungal) that would then be tested in clinical trials for its ability to treat coccidioidomycosi with superiority to current therapy and thus serve as a safeguard against use of Coccidioides as a biological weapon. PUBLIC HEALTH RELEVANCE: This project addresses the limitations of current therapy to treat the deadly infection coccidioidal meningitis (CM) caused by Coccidioides, a fungus which can be weaponized and used in a bioterrorist attack. This disease is 100% lethal if untreated, and current therapy has a 40% mortality rate. The ultimate goal of this research is to identify an oral antifungal agent that has a significantly lower mortality rate and that could be stockpiled in advance of an attack. Achieving this goal would both minimize the incentive to use Coccidioides as a biological weapon and also directly impact on the health of patients with naturally occurring infections. The specific goals of the research are to build a strong argument to pursue clinical studies of VT-1161 in the treatment of coccidioidomycosis or to identify a molecule with even a higher chance of reaching the ultimate clinical goal of superiority over current therapy.